A gold standard for breast cancer treatment

Some 3,600 years ago, the island of Santorini (Thera) – about 120 miles south of mainland Greece in the Aegean Sea – blew its top. In the most cataclysmic volcanic eruption in the recorded history of our planet, 30 cubic kilometres of magma, in the form of pumice and volcanic ash, buried the island and its civilisation.

These dramatic events have given rise to a number of legends and myths. Firstly, the destroyed civilisation of the island of Strongili, as Thera was known before the eruption, gave rise to the legend of the lost city of Atlantis. The apparent sudden destruction of the Minoan civilisation on the island of Crete has been ascribed to this catastrophic event and the tsunami that followed in its wake. Finally, the timing of the volcanic eruption was undoubtedly close to the timing of the exodus of the Jews from ancient Egypt and a rational explanation for the 10 plagues described in the Old Testament. Some of the events that would be predicted to accompany a volcanic eruption of this magnitude might account for the plagues. For example, the column of ash above the volcano could produce a shadow long enough for the sun to be obliterated at noon over ancient Egypt. Furthermore, the inflow of the Mediterranean Sea into the volcanic cavity followed by the mighty tsunami, might have accounted for the dry crossing of the Red Sea by Moses and the children of Israel, followed by the destruction of Pharaoh and his legions shortly thereafter. Bible stories and legends of lost civilisations are romantic, but the dramatic reality might exceed the expectations of many sceptics.

Approximately 10 years ago, a shaft was being dug to provide foundations for a permanent protective cover over the archaeological excavations at Akrotiri, a site at the southern tip of the crescent-shaped island. Amongst the rubble, a workman discovered a perfectly preserved wooden box that was thought to serve some late Bronze Age domestic role. On opening the box, the archaeologists were astonished to discover a most beautifully crafted and perfectly preserved golden ibex about the size of a newborn kitten. Closer inspection revealed that it was hollow with all four limbs welded at the junction with the trunk. The technique for welding the limbs onto the trunk was a mystery, as was the object’s role within this lost civilisation.

As an object, this sublimely proportioned artefact can be looked upon in three ways. Firstly, as an object venerated for its beauty and, for all we know, venerated in its time as a household God, a pocket-sized adumbration of the Golden Calf worshipped by the children of Israel a few years after the exodus from Egypt. Secondly it could be looked upon as an archaeological curiosity capable of throwing light on the Bronze Age civilisations of the Cicladean Islands and their trading links with ancient Egypt to the south and the biblical kingdoms to the east. Finally, it was a technological challenge to assay the gold and interpret the technique for joining the limbs to the trunk without damaging the find.

In the last week of August 1997, a group of us assembled on the island as guests of Peter Nomikos, the founder of Photoelectron Corporation, for a scientific advisory board meeting. I had been working with Photoelectron Corporation for about three years developing a technique for intra-operative radiotherapy in the treatment of early breast cancer, using a miniature X-ray generating source developed by the company. This device, about the size and the shape of a woman’s handbag, accelerates electrons down a metallic capillary tube, which then hit a gold target. This generates soft X-rays from a point source at its tip. Introduced within the cavity following wide local excision of an early breast cancer, it can deliver a full booster dose of radiation to the excision margins; I’ll expand on this shortly. The Nomikos Foundation also supports the archaeological explorations of Akrotiri and, for that reason, I was privileged to witness an historic first in the history of archaeology.

On Sunday 31 August, a group consisting of archaeologists, technologists and oncologists gathered in the subterranean laboratories of the archaeological museum in Thera. Also in our number was the great pianist and conductor, Vladimir Ashkenasy, another house guest of the Nomikos family. The Golden Ibex was placed upon a laboratory table and the miniature X-ray source was directed precisely at the weld at the junction between a hind-limb and the trunk of this enigmatic beast. The device was switched on, electrons were accelerated down the capillary tube and X-rays from the gold target at the tip of the device excited the molecules within the Bronze Age weld of the ancient gold of the Ibex. The signal from the excitation of these molecules was then picked up by another extraordinary technological invention developed for the NASA Mars exploration project. This detection probe then provided us with a waveform printout describing the precise content of the solder.

Thus, with the benefits of modern technology, the artisan of an ancient Cicladean culture was able to speak to us over the centuries. It is difficult to describe the sense of wonder we all experienced at this unique amalgam of art, archaeology and technology. The results from this experiment were quite remarkable and confirmed that the artisan was a visitor from ancient Egypt in the second millennium BC. The Golden Ibex was buried at the time of the biblical exodus from Egypt. To think that I handled a household god manufactured by a similar technique to, and within a few years of, the Golden Calf at the foot of Mount Sinai, still makes my hair prickle on the back of my neck.

So how did all this come about and what is the relevance to the treatment of breast cancer? One of the undoubted charms of research is the making of connections from random observations often from disciplines other than your own. Another useful asset is the gift of serendipity. Two events collided that have led to a very important breakthrough in the management of breast cancer: one personified by Peter Nomikos and the other personified by Jayant Vaidya.

Peter is the doyen of a great Greek shipping family, a charming, elegant and aristocratic man. His beautiful wife Dola shares the same qualities. Between them, they own most of the land of Santorini and enjoy a friendly competition in the production of fine white wines. They own the castle and its complex of pools, gardens and habitable caves that dominates the skyline visible as the cruise ships enter the harbour. This golden couple’s life was blighted by the loss of one of their children at the age of 11 from a virulent form of cancer and Peter always wanted to give something back to the oncology community as a fitting memorial for their son.

Peter also owned a small hi-tech company in the USA. His physicists invented a miniature electron generator and found themselves with ‘a technology for which there was no known disease’, although their original idea was to use in the treatment of brain tumours. As I had treated one of their friends for breast cancer, Peter and his physicist came to visit me shortly after I was appointed to the chair in surgery at University College London in 1995. The challenge they offered was to use the technology for the management of early breast cancer.

Around about the same time, another interesting character entered my sphere of influence. About a year before, my old friend Indraneel (Neel) Mittra, the head of the breast cancer centre at the Tata Memorial Hospital in Mumbai, asked me to take a look at one of his postgraduate students, Jayant (Jay) Vaidya, who he claimed was the brightest young medical graduate from the whole of India. Neel thought that I might find it worthwhile to take him on as a PhD student. My first impressions of Jay were not auspicious. He wore a shapeless suit, the scruffiest of shoes and spoke with an almost impenetrable Indian accent.

However it didn’t take long to learn that, in his own way, he was a bit of an aristocrat. The name Vaidya describes his origins from a long line of traditional ayurvedic healers. Jay’s grandfather is honoured with a statue in the central square of Goa and his late and lamented father, a public health doctor, was a great man who single-handedly and successfully campaigned to make Goa the first tobacco-free state in the world.

The next thing I learnt about Jay was his incandescent intelligence. One piece of work he had completed in Mumbai shortly before coming to the UK concerned the ‘multi-focality’ of breast cancer. At this time, the default therapy for early breast cancer was ‘lumpectomy’ – the removal a discrete cancer with the aim of preserving the breast – and it was assumed that following surgery the whole of the breast had to be treated with six weeks of post-operative radiotherapy to mop up any remnants of disease outside the vicinity of the primary cancer.

Jay’s study involved a careful analysis of several hundred mastectomy specimens cutting them in 50 thin slices and then mapping out according to three dimensional co-ordinates the number and position of areas of cancer outside the primary focus, that were unsuspected on clinical and radiological grounds. These areas weren’t just a few cells, but fully formed foci of in situ or invasive disease below the threshold of size for mammographic detection. Over 60 per cent of breasts had these hidden foci and most of them were well away from the dominant (index) primary.

Most readers would then jump to the conclusion that this was a vindication of the policy of whole breast radiation. Paradoxically, however, after breast-conserving surgery the results of most observational studies or clinical trials have demonstrated that 90 per cent of recurrent disease in the breast after surgery is in the vicinity of the original tumour, regardless of whether radiotherapy had been applied to the whole breast. This counter-intuitive observation has both biological and clinical consequences. Biologically, this tells us that not all that looks like cancer under the microscope will behave like cancer. The clinical consequence of this observation suggests that maybe we don’t have to apply radiotherapy to the whole breast, but only to the immediate area around the tumour after it has been removed. If that is the case, then this opened up the possibility of removing the tumour and applying radiation to the cavity left behind immediately afterwards.

After two years of research and development, we had developed a prototype for the first clinical trial. This consisted of a gantry that would hold the device steady in three-dimensional space. In addition, we had manufactured for us a selection of applicators with a hollow sphere at the end. The idea was that the electrons would be accelerated down a metal capillary tube hitting a gold target at its tip. This bombardment would release X-rays that would spread out in a spheroidal configuration. The tip of the tube sat precisely at the epicentre of the spheroidal plastic applicator of a size chosen to fit the cavity after the tumour was excised. This way the walls of the tumour cavity would be irradiated to a very high dose that rapidly diminished over a distance of a few centimetres, protecting both the patient’s vital organs and the equipment operator and making the device safe to use in any operating theatre.

A very courageous lady with a small breast cancer volunteered to be the first patient and neither of us had a good night’s sleep before the morning of the operation. With my dear friend Jeff Tobias, the radiotherapist and his team of physicists standing by, Jay on the other side of the operating table, and my heart somewhere close to my epiglottis, I cut out the tumour and stopped the bleeding. I then chose an applicator with a sphere that fitted snugly in the cavity, inserted the electron beam tube, turned on the machine and stepped out of the theatre for 25 minutes leaving the anaesthetist, in theory, out of range.

Sometimes you have to get lucky as well as getting good. As chance would have it the surface of the applicator and the surface of the interior of the breast adhered to each other which meant the geometric conformation of the radiation to the target was perfect. Next, as predicted, the anaesthetist’s radiation badge showed no fogging, so he may yet father children, and, finally, the crude guess at the appropriate dose of X-rays to administer proved to be correct. The next night, I couldn’t sleep as I considered the implications of this tentative step forward. Meanwhile the patient slept well and made a full and uneventful recovery.

The implications of this leap in the dark are profound. If it works out, then many women will be spared seven weeks of treatment traipsing back and forwards to the radiotherapy centre. Furthermore, tens of thousands of women in the developing world who live hundreds of miles from a radiotherapy unit or in countries that can’t afford the multi-million pound investment, will be able to enjoy the advantages of breast conservation, by bringing the radiotherapy unit to the patient.

In countries like ours, the waiting list for post-operative radiotherapy would vanish at a stroke and we estimate the National Health Service would be saved £15million per year. So far, 300 women have been treated in pilot studies and followed up for five years, without ill effect and with a remarkably low local recurrence rate. We also have a multinational clinical trial of intra-operative radiotherapy alone versus conventional post-operative radiotherapy that has, at the time of writing, recruited about 2,000 patients. Twenty-five collaborating centres are dotted round the world from Europe to California to southwest Australia. I suspect that we will identify groups of women where the one shot of X-rays at the time of surgery is just as effective as the exhausting three-to-six weeks of conventional treatment. Radiobiological studies led by Professor Frederik Wenz of Mannheim University even suggest the novel approach might be better.

Sadly the first casualty of the programme was Photoelectron Corporation, which went into receivership. Fortunately the Carl Zeiss Corporation in Germany was able to step in and manufacture what is now known as INTRABEAM. Finally, as I retire from clinical practice, I am indeed fortunate that Jay Vaidya was ready to take my place, now smartly dressed, shoes polished, accent improved and brain as sharp as ever.

The golden ibex of Santorini may yet turn out to be an omen of good luck for the thousands of women who will inevitably develop breast cancer in decades to come.

Michael Baum worked for 30 years as a surgeon specialising in breast cancer, and is now professor emeritus of surgery at University College London.

This is an extract from Breast Beating: A Personal Odyssey in the Quest for an Understanding of Breast Cancer, the Meaning of Life and Other Easy Questions, by Michael Baum, published by Anshan. (Buy this book from Amazon(UK).)